Besides safety and ethical issues, there are multiple challenges to developing a neonatal HIV vaccine. Because a considerable rate of transmission occurs during the first 6 months, an HIV vaccine must rapidly elicit protective immune responses, even in the presence of maternal antibodies. In addition, because breast- feeding infants are at risk to acquire HIV infection throughout the breast-feeding period, a vaccine given early after birth needs to give long-term immunity (many months to several years). Understandably, there is reluctance to perform HIV vaccine studies in infants before efficacy, or even immunogenicity, of a vaccine candidate is demonstrated in adults. However, adult responses to vaccines cannot be assumed to reliably predict vaccine immunogenicity or effectiveness in children and infants. In additon, the HIV vaccine regimens currently being evaluated in adults appear to elicit immunity too slowly to prevent postnatal HIV transmission or pediatric AIDS. Thus, studies of the immunogenicity and efficacy of HIV vaccines with a rapid immunization schedule are essential to developing a vaccine to prevent HIV breast milk transmission; however, such studies are extremely technically demanding and ethically challenging. Our proposed project will use the SIV/neonatal rhesus macaque model of pediatric HIV/AIDS to evaluate immunogenicity and efficacy of candidate HIV vaccine strategies in infant primates. Infant rhesus macaques are uniquely suited to provide information needed to develop vaccines against vertical HIV transmission and pediatric AIDS, because of the many similarities in human and macaque physiology, immunology, and disease pathogenesis. Like human infants, newborn rhesus macaques are competent to develop virus-specific immune responses after vaccination, including vaccination with live-attenuated SIV. Results from our proposed project can be applied directly to design vaccines to prevent HIV infection or disease in human newborns and children. The overall goals of the proposed project are to evaluate the ability of two replicating, attenuated SIV vaccine strategies [(1) Vesicular Stomatitis Virus and Modified Vaccinia Ankara expressing SIV antigens, VSV-SIV + MVA-SIV, and (2) nonpathogenic SIVmacIA11] to : (Aim1) elicit SIV-specific immunity in rhesus neonates; (Aim 2) protect against subsequent oral SIV challenge and;(Aim3) determine in vivo immune correlates of the efficacy of these active vaccine regimens.